Metabolic issues during the covid-19 pandemic: Gender difference

Abstract

The coronavirus disease 2019 (COVID-19) has rapidly spread all over the world, causing a great number of casualties. From the very beginning of the pandemic, it has become apparent that there are multiple risk factors associated with an increased risk of disease severity and death. These include older age, smoking and several underlying comorbidities, as well as gender.1 Susceptibility for SARS-CoV-2 infection appears to be similar in men and women, and yet most of the clinical and epidemiological data has shown that almost twice as many men with COVID-19 suffer severe symptoms or death as women.2 Despite a similar incidence between the two genders, men consistently show a more severe phenotype and an increased mortality rate (62.4%) across age groups at global level.3 A large population-based study performed in England, which included over 17 million adults and 10,926 COVID-19-related deaths, found that males had a significantly higher risk of death (HR 1.59; 95% CI, 1.53-1.65) than females.4 A recently published review reported that, overall, males account for 59-75% of all COVID-19 deaths.5 Sexual dimorphism in COVID-19 should not come as a surprise, because it is well known that men and women respond to viral infections differently, as already reported during other flu outbreaks.6 Many of the genes playing a key role in the immune response are located on the X chromosome, including those involved in determining the innate and adaptive immune responses to viral infections.7 Interestingly, gene encoding for the ACE2 receptor – through which SARS-CoV-2 binds to the cell membrane and enters the host cell – is also located on the X chromosome, so that a higher degree of protein expression could be expected in the female gender, which may increase the risk of viral infection.8 However, a higher ACE2 activity – particularly in the lungs and in the cardiovascular system – has been claimed to confer some protection, which may account for the less severe form of COVID-19 in women.9 Consistent with this hypothesis is the finding that the male heart has less ACE2-expressing cells than the female one,10 which provides support to a sex-specific regulation of ACE2. Nevertheless, such sex-dependent ACE2 expression has not yet been validated in humans, and no relevant influence of medications such as ACE-inhibitors has been documented. Sex differences in the manifestation of infectious diseases have long been attributed also to the influence of sex hormones. Experimental work performed in a murine model of SARS-CoV-2 infection has shown that male animals were more susceptible to infection and had higher mortality than females. Interestingly, the estrogen deprivation obtained by ovariectomy nullified this protection, causing an increase in mortality.11 These results indicate how the balance between androgens and estrogens is likely to play an important role in modulating immune responses in coronavirus infections. Conversely, men receiving androgen deprivation therapy seem to be protected from SARS-CoV-2 infection, which further supports the concept of sexual dimorphism in response to the SARS-CoV-2 infection.12 A gene expression study on the immune system of mice indicated that this sexual dimorphism is mainly limited to macrophages, with an up-regulation of macrophages-specific genes (eg., complement-related and IFN-stimulated genes) found in female cells.13 Thus, females could show a more activated innate response pathway prior to an infection with a pathogen. Furthermore, TLR7 signaling and IFN production seem to be more expressed in females, while estrogen also increases TLR7 expression. Finally, the immune system has been implicated in driving a detrimental and dysregulated inflammation in COVID-19,14 therefore it may seem counterintuitive that males are at greater risk of COVID-19 hyperinflammation, considering that females have been described to mount stronger immune responses to viral infections. This highlights once again the complexity of the differences between the male and female immune systems, and their responses to infection. In summary, infection rates appear to be similar between men and women, although the response to infection differs between the sexes. It has been suggested that anti-viral responses and viral clearance, mediated by IFN and TLR7, are increased in females, contributing to the reduced COVID-19 mortality observed in women compared with men. In men, dysregulated inflammation and an increased cytokine release are likely to be responsible for the increase in ARDS, respiratory failure Metabolic issues during the COVID-19 pandemic: gender difference